Recessive Stargardt disease phenocopying hydroxychloroquine retinopathy

Nõupuu, Kalev; Lee, Winston; Zernant, Jana; Greenstein, Vivienne C.; Tsang, Stephen H.; Allikmets, Rando

doi:10.1007/s00417-015-3142-8

Cited by 16 publications

(14 citation statements)

References 36 publications

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“…The finding of a mutation (p.N1868I) that is consistently associated with foveal sparing could lead to identification of those mechanisms. 39 Many, but not all the patients in this cohort maintained foveal sparing (and the attendant good visual acuity) up to their latest follow-up visit. Any preventative treatment of this group would need to balance the risk of treating some of these patients who might not lose significant acuity for several years untreated, with the potential benefits to those who eventually do lose their foveal sparing.…”

Section: Resultsmentioning

confidence: 79%

CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION

Collison¹,

Lee

Fishman

et al. 2019

Retina

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Purpose: To investigate the Stargardt disease phenotype associated with an unusually common and “extremely hypomorphic” ABCA4 variant, p.N1868I. Methods: The charts of 27 patients with p.N1868I on one allele and a severe/deleterious mutation on the other allele were reviewed. Subjective age of onset, best-corrected visual acuity, and stage of disease were recorded for all 27 patients, 18 of whom had multiple visits. When available, fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, full-field electroretinograms, Goldmann visual fields, and fluorescein angiography were included. Five families with multiple affected members were analyzed. Results: The median age at symptom onset was 41.5 years, and 3 p.N1868I patients had not developed visual symptoms as of the most recent eye examination. Median best-corrected visual acuity in the better-seeing eye at baseline was 20/25−2, and the median duration from symptom onset to legal blindness was 25 years. The five families described in this study demonstrated clinically significant intrafamilial variability, and affected family members who did not share the p.N1868I variant had relatively more severe phenotypes. Conclusion: This study demonstrates the consistency of foveal sparing, the variation in age at onset, the intrafamilial variability, and the prognosis with regard to visual acuity in p.N1868I-associated Stargardt disease.

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Section: Resultsmentioning

confidence: 79%

CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION

Collison¹,

Lee

Fishman

et al. 2019

Retina

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“…47 The phenotype of HCQ toxicity is similar to cases of ABCA4 disease (STGD1) that manifest as a BEM. 48 An National Eye Institute (NEI) clinical trial is currently recruiting patients for a genotype-phenotype study of HCQ-induced retinal toxicity and involvement of the ABCA4 gene (ClinicalTrials.gov identifier: NCT01145196). As in ABCA4-related retinal disease, if an association between ABCA4 variants and HCQ 47 were to exist, it may be explained by levels of bisretinoid lipofuscin.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Fundus Autofluorescence in HCQ Retinopathy

Greenstein

Carvalho

Parmann

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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To increase our understanding of the mechanisms underlying hydroxychloroquine (HCQ) retinopathy, analyses by quantitative fundus autofluorescence (qAF) and near-infrared fundus autofluorescence (NIR-AF) were compared to results obtained by recommended screening tests. METHODS. Thirty-one patients (28 females, 3 males) were evaluated with standard automated perimetry and spectral domain optical coherence tomography (SD-OCT); 28 also had multifocal electroretinography (mfERG). Measurement of short-wavelength fundus autofluorescence (SW-AF) by qAF involved the use of an internal fluorescent reference and intensity measurements in eight concentric segments at 7°to 9°eccentricity. For semiquantitative analysis of NIR-AF, intensities were acquired along a vertical axis through the fovea. RESULTS. Four of 15 high-dose (total dose >1000 g, daily dose >5.0 mg/kg) patients and one of 16 low-dose (total dose <1000 g, daily dose 4.4 mg/kg) patients were diagnosed with HCQ-associated retinopathy based on abnormal 10-2 visual fields, SD-OCT, and SW-AF imaging. Three of the high-dose patients also had abnormal mfERG results. Of the five patients exhibiting retinopathy, two had qAF color-coded images revealing higher intensities inferior, nasal, and lateral to the fovea. The abnormal visual fields also exhibited superior-inferior differences. Mean NIR-AF gray-level intensities were increased in four high-dose patients with no evidence of retinopathy. In two patients with retinopathy, NIR-AF intensity within the parafovea was below the normal range. One high-dose patient (6.25 mg/kg) had only abnormal mfERG results. CONCLUSIONS. These findings indicate that screening for HCQ retinopathy should take into consideration superior-inferior differences in susceptibility to HCQ retinopathy.

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“…Moreover, some maculopathies are also caused by environmental factors, such as drug-toxicity (e.g. hydroxychloroquine) ( Noupuu et al, 2016 ; Shroyer et al, 2001a ), light damage, etc. Therefore, it is often practically impossible to determine the cause of a maculopathy without comprehensive genetic screening.…”

Section: Phenocopies Of Abca4 -Associated Retinopamentioning

confidence: 99%

Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations

Cremers

Lee

Collin

et al. 2020

Progress in Retinal and Eye Research

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227

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The ABCA4 protein (then called a “rim protein”) was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4 , was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types – missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy – clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches.

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Recessive Stargardt disease phenocopying hydroxychloroquine retinopathy

Cited by 16 publications

References 36 publications

CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION

CLINICAL CHARACTERIZATION OF STARGARDT DISEASE PATIENTS WITH THE p.N1868I ABCA4 MUTATION

Quantitative Fundus Autofluorescence in HCQ Retinopathy

Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations

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